273
drop in AMA (anti-M2) titre after liver transplantation is well described, and some patients even lose the antibody entirely.4 There is no clear relation between the antibody titre and any clinical feature of PBC. Although titres are higher in patients with symptoms than in those without,5there is no evidence that the height of the antibody titre predicts outcome. AMA is often present in family members who have no evidence of liver disease, and immunoblotting techniques have failed to show any qualitative difference between the antibody in PBC patients and in non-PBC individuals.66 These observations suggest that AMA is unlikely to be closely related to pathological changes in the liver.
testify to the success and value of this procedure in prolonging and providing good quality life. Perhaps the most important consequence of the controversy is that it may help to shed light on the pathogenesis of PBC. To supporters of the autoimmune aetiology for the disease the possibility of recurrence will not come as a surprise; they will advocate immunosuppressants such as azathioprine and cyclosporin, which should be used early if they are to be effective. On the other hand, evidence is emerging to suggest that the AMA, and by implication perhaps even PBC itself, may have a bacterial component to its aetiology, 11 in which case the logical approach to prevention should be very
A similar argument can be advanced for the raised serum IgM, which is present in 80% of patients with PBC. IgM is commonly increased in family members of PBC patients,’ and in PBC itself the immunoglobulin abnormality reflects a failure to switch antibody production from IgM to IgG owing to a T-cell defect which is probably independent of the liver diseased The histological changes described by Polson et all include bile ductular proliferation, lack of bileducts, lymphoid aggregation in the portal tracts, and granulomas. These features are undoubtedly consistent with the diagnosis of PBC outside the context of liver transplantation, but are also recognised in association with organ rejection and graft-versus-host disease. Infection of the reconstructed biliary tract is also a serious and frequent complication of liver transplantation: although the histological appearance of the liver does not resemble that seen in PBC, the features may be influenced by the immunosuppressants that these patients receive. The combination of a positive AMA, raised alkaline phosphatase and serum IgM, and histological changes consistent with PBC is conclusive evidence in a newly presenting patient, but it cannot be assumed that the same criteria pertain in one who has undergone liver transplantation.
different. If PBC does recur, and if this process bears any resemblance to the evolution of the disease in the first place, then we may have stumbled on a novel means of studying the development of this disorder.
The
If PBC recurs,
why has recurrence been reported only from England? Starzl’s group in Pittsburgh were unable to show disease recurrence in 76 patients followed for up to 6-5 years,9no while no recurrence was observed among 9 patients in whom biopsies were done annually for 5 years from Germany.4However, as Polson and colleagues argue, the American report is based on clinical experience alone with few long-term follow-up biopsies, and the histological changes of PBC are likely to antedate the signs and symptoms by several years. An interesting difference between the Pittsburgh and Cambridge transplant programmes is that in America duct-to-duct anastomosis of the biliary tree is usually carried out whereas the English group favour the construction of a biliary conduit. The possibility of recurrence in the transplanted organ should not influence decisions about the value of hepatic transplantation as the treatment of choice for advanced PBC since there is already enough
evidence
to
Portmann B, MacDougall BRD, Calne RY, Williams R. Recurrence of primary biliary cirrhosis after liver transplantation. N Engl J Med 1982; 306: 1-4. 2. Polson RJ, Portmann B, Neuberger J, Calne RY, Williams R. Evidence for disease recurrence after liver transplantation for primary biliary cirrhosis. Gastroenterology 1989; 97: 715-25. 3. Wiesner RH, Ludwig J, Lindor KD, et al. A controlled trial of cyclosporin in the treatment of primary biliary cirrhosis. N Engl J Med 1.
Neuberger J,
1990; 322: 1419-24. Haagsma EB, Manns M, Klein R, et al. Subtypes of antimitochondrial antibodies in primary biliary cirrhosis before and after orthotopic liver transplantation. Hepatology 1987; 7: 129-33. 5. Roll J, Boyer JL, Barry D, Klatskin G. The prognostic importance of clinical and histological features in asymptomatic and symptomatic primary biliary cirrhosis. N Engl J Med 1983; 308: 1-7. 6. Fusconi M, Ghadiminejad I, Bianchi FB, et al. Heterogeneity of antimitochondrial antibodies with the M2-M4 pattern by immunofluorescence as assessed by western immunoblotting and
4.
enzyme linked immunosorbent assay. Gut
1988; 29: 440-47.
7.
Salaspuro MP, Laitinen DI, Lehtola J, et al. Immunological parameters, viral antibodies and biochemical and histological findings in patients with chronic active hepatitis and primary biliary cirrhosis. Scand J
8.
Watmough D, French MAH, Triger DR. Antibody response to tetanus toxoid in patients with primary biliary cirrhosis. J Clin Pathol 1987; 70:
Gastroenterol 1976; 11: 313-20.
683-86.
Esquivel CO, Van Thiel DH, Bernados A, et al. Liver transplantation for primary biliary cirrhosis. Gastroenterology 1988; 94: 1207-16. 10. Demetris AJ, Markus BH, Esquivel C, et al. Pathologic analysis of liver transplantation for primary biliary cirrhosis. Hepatology 1988; 8: 9.
939-47. 11. Sternerowicz R, Hopf U, Möller B, et al. Are antimitochondrial antibodies in primary biliary cirrhosis induced by R (rough)-mutants of Enterobacteriaceae? Lancet 1988; ii: 1166-70.
Zinc sandwich Why should primate growth hormones, unlike those of other vertebrates, have lactogenic activity? This question has puzzled endocrinologists for many years. Now Cunningham and his fellow protein engineers1 at Genentech in San Francisco think they may have found the answer-zinc. This trace metal is already known to be an essential component of the zinc finger regulatory proteins of the steroid receptor superfamily that includes oestrogen, progesterone, thyroid hormone, and 1,25-dihydroxyvitamin D receptors.2,3 These are cytoplasmic receptors and the hormones must pass through the plasma membrane to interact with them. By contrast, peptide hormones
274
their effects by combining with specific cellsurface receptors. Non-primate growth hormones show weak or undetectable binding to extracellular prolactin receptors. The Genentech researchers began their investigations by cloning the binding domain of the human prolactin receptor and then established that 50 jmol/1 zinc chloride enhanced the binding affinity of human growth hormone (hGH) for this extracellular receptor 8000-fold. Binding of hGH to the hGH receptor and of human prolactin to the prolactin receptor was not zinc dependent. Probable zinc ligands were shown to be a three-residue clusterHis, HisZl, and Glul74-in the hGH receptor and Hisl88 in the human prolactin receptor; non-primate growth hormones contain His21 and Glu 174 but instead of HisI8 they have Gln18. The hormone receptor zinc sandwich not only explains why non-primate growth hormones do not have lactogenic activity but also may shed light on other endocrine effects of zinc-eg, the link between zinc deficiency and growth retardation. Since growth hormone and prolactin receptors belong to the same family as peptide regulatory factor receptors, zinc may mediate receptor interaction of the interleukins, erythropoietin, and colony stimulating factors. exert
1.
Cunningham BC, Bass S, Fuh G, Wells JA. Zinc mediation of the binding of human growth hormone to the human prolactin receptor.
Science 1990; 250: 1709-12. 2. Evans RM. The steroid and thyroid hormone receptor superfamily. Science 1988; 240: 889-95. 3. Editorial. Zinc fingers and vitamin D resistance. Lancet 1989; i: 478.
Placental localisation in early pregnancy When women undergo ultrasound scanning in early pregnancy to clarify the gestational age or to screen for structural malformation in the fetus, an incidental finding may be a low-lying placenta-the placenta reaches or overlies the cervical os in 5%1,2 to 26 %of cases. That the frequency is lower if the initial scan is conducted at 20 weeks than if it is done early4 does not seem to explain all of this variation. Different criteria may have been used to categorise cases; researchers who describe a placenta as low lying only if it is seen to cover the cervical os, at least partly, report a frequency of 5-6%.12 Very few of the women identified in this way will have placenta praevia at delivery, presumably because growth of the uterus outstrips that of the placenta. Nevertheless, it has been arguedl,2,4-6 that they should be rescanned for placental site in the third trimester, at 28-36 weeks. This argument is based on a delivery frequency of placenta praevia of 2’3%4 to 16-9% in this group, compared with the population frequency of less than 1%. It is not clear why there should be such a large variation in the rate at which the condition is present at delivery in women diagnosed initially as high risk.
Other workers who have carried out prospective studies have concluded that, because so few women found to have a low placenta on the first scan still manifest the condition at delivery (2%,’ 0%1-3%), third-trimester scanning for this group cannot be justified unless there are clinical indications such as vaginal bleeding or unstable lie. These studies also provided data on whether all the clinical cases of placenta praevia noted in hospital had been diagnosed by the booking scan. Mc Clure and Doman,3 who conducted the largest and most recent study (also the one with the highest rate of low-lying placenta on initial ultrasound scanning), found that only 18 of 30 clinical cases had been so predicted, and agreed with previous proposals that a low-lying placenta on the initial scan should be ignored. Because of the high morbidity associated with placenta praevia and because bleeding does not necessarily occur before the onset of labour,l the possibility of early detection is attractive. However, the sensitivity and specificity of low-lying placenta on the first scan, as a test for clinical placenta praevia at delivery, are very poor. Many women, informed of the result and asked to reattend, become unduly worried that, if the repeat scan still shows a low-lying placenta, they may be advised to restrict activity, or be admitted. Placental localisation is important in women who have appreciable or recurrent vaginal bleeding and in those with an unstable lie in late pregnancy. The index of suspicion should be higher in older women of high parity, especially if there is a history of caesarean section9-11 (because such patients have an enhanced risk of placenta praevia and placenta accreta) and in those with a history of placenta praevia.12 Placental localisation at the initial scan cannot be recommended, and when a low placenta is noted incidentally, it is not necessary routinely to order a third-trimester scan. N, Doran TA, Miskin M, Benzie RJ, Ford JA. Natural history of placenta previa ascertained by diagnostic ultrasound. Am J Obstet Gynecol 1979; 133: 287-91. 2. Varma TR. The implications of low implantation of the placenta detected by ultrasonography in early pregnancy. Acta Obstet Gynaecol Scand 1. Rizos
1981; 60: 265-68. 3. McClure N, Dornan JC. Early identification of placenta praevia. Br J Obstet Gynaecol 1990; 97: 959-61. 4. Comeau J, Shaw L, Marcell CC, Lavery JP. Early placenta previa and delivery outcome. Obstet Gynecol 1983; 61: 577-80. 5. Royal College of Obstetricians and Gynaecologists. Report of the RCOG Working Party on Routine Ultrasound Examination in Pregnancy. London: RCOG, 1984. 6. Langlois SL, Miller AG. Placenta praevia: a review with emphasis on the role of ultrasound. Aust NZ J Obstet Gynaecol 1989; 29: 110-16. 7. Ruparelia BA, Chapman MG. Early low-lying placentae—ultrasonic assessment, progress and outcome. Eur J Obstet Gynecol Reprod Biol 1985; 20: 209-13. 8. Anderson ES, Steinke NM. The clinical significance of asymptomatic midtrimester low placenta diagnosed by ultrasound. Acta Obstet Gynaecol Scand 1988; 67: 339-41. 9. Singh PM, Rodrigues C, Gupta AN. Placenta praevia and previous caesarean section. Acta Obstet Gynaecol Scand 1981; 292: 371-72. 10. Breen JL, Neubecker R, Gregori CA, Franklin JE. Placenta accreta, increta and percreta: a survey of 40 cases. Obstet Gynecol 1977; 49: 43-47. 11. Clark SL, Koonings PP, Phelan JP. Placenta previa/accreta and prior cesarean section. Obstet Gynecol 1985; 66: 89-92. 12. Godoreski IG, Bahari CM, Schachter A, Neri A. Recurrent placenta previa. Eur J Obstet Gynecol Reprod Biol 1981; 12: 7-11.
drop in AMA (anti-M2) titre after liver transplantation is well described, and some patients even lose the antibody entirely.4 There is no clear relation between the antibody titre and any clinical feature of PBC. Although titres are higher in patients with symptoms than in those without,5there is no evidence that the height of the antibody titre predicts outcome. AMA is often present in family members who have no evidence of liver disease, and immunoblotting techniques have failed to show any qualitative difference between the antibody in PBC patients and in non-PBC individuals.66 These observations suggest that AMA is unlikely to be closely related to pathological changes in the liver.
testify to the success and value of this procedure in prolonging and providing good quality life. Perhaps the most important consequence of the controversy is that it may help to shed light on the pathogenesis of PBC. To supporters of the autoimmune aetiology for the disease the possibility of recurrence will not come as a surprise; they will advocate immunosuppressants such as azathioprine and cyclosporin, which should be used early if they are to be effective. On the other hand, evidence is emerging to suggest that the AMA, and by implication perhaps even PBC itself, may have a bacterial component to its aetiology, 11 in which case the logical approach to prevention should be very
A similar argument can be advanced for the raised serum IgM, which is present in 80% of patients with PBC. IgM is commonly increased in family members of PBC patients,’ and in PBC itself the immunoglobulin abnormality reflects a failure to switch antibody production from IgM to IgG owing to a T-cell defect which is probably independent of the liver diseased The histological changes described by Polson et all include bile ductular proliferation, lack of bileducts, lymphoid aggregation in the portal tracts, and granulomas. These features are undoubtedly consistent with the diagnosis of PBC outside the context of liver transplantation, but are also recognised in association with organ rejection and graft-versus-host disease. Infection of the reconstructed biliary tract is also a serious and frequent complication of liver transplantation: although the histological appearance of the liver does not resemble that seen in PBC, the features may be influenced by the immunosuppressants that these patients receive. The combination of a positive AMA, raised alkaline phosphatase and serum IgM, and histological changes consistent with PBC is conclusive evidence in a newly presenting patient, but it cannot be assumed that the same criteria pertain in one who has undergone liver transplantation.
different. If PBC does recur, and if this process bears any resemblance to the evolution of the disease in the first place, then we may have stumbled on a novel means of studying the development of this disorder.
The
If PBC recurs,
why has recurrence been reported only from England? Starzl’s group in Pittsburgh were unable to show disease recurrence in 76 patients followed for up to 6-5 years,9no while no recurrence was observed among 9 patients in whom biopsies were done annually for 5 years from Germany.4However, as Polson and colleagues argue, the American report is based on clinical experience alone with few long-term follow-up biopsies, and the histological changes of PBC are likely to antedate the signs and symptoms by several years. An interesting difference between the Pittsburgh and Cambridge transplant programmes is that in America duct-to-duct anastomosis of the biliary tree is usually carried out whereas the English group favour the construction of a biliary conduit. The possibility of recurrence in the transplanted organ should not influence decisions about the value of hepatic transplantation as the treatment of choice for advanced PBC since there is already enough
evidence
to
Portmann B, MacDougall BRD, Calne RY, Williams R. Recurrence of primary biliary cirrhosis after liver transplantation. N Engl J Med 1982; 306: 1-4. 2. Polson RJ, Portmann B, Neuberger J, Calne RY, Williams R. Evidence for disease recurrence after liver transplantation for primary biliary cirrhosis. Gastroenterology 1989; 97: 715-25. 3. Wiesner RH, Ludwig J, Lindor KD, et al. A controlled trial of cyclosporin in the treatment of primary biliary cirrhosis. N Engl J Med 1.
Neuberger J,
1990; 322: 1419-24. Haagsma EB, Manns M, Klein R, et al. Subtypes of antimitochondrial antibodies in primary biliary cirrhosis before and after orthotopic liver transplantation. Hepatology 1987; 7: 129-33. 5. Roll J, Boyer JL, Barry D, Klatskin G. The prognostic importance of clinical and histological features in asymptomatic and symptomatic primary biliary cirrhosis. N Engl J Med 1983; 308: 1-7. 6. Fusconi M, Ghadiminejad I, Bianchi FB, et al. Heterogeneity of antimitochondrial antibodies with the M2-M4 pattern by immunofluorescence as assessed by western immunoblotting and
4.
enzyme linked immunosorbent assay. Gut
1988; 29: 440-47.
7.
Salaspuro MP, Laitinen DI, Lehtola J, et al. Immunological parameters, viral antibodies and biochemical and histological findings in patients with chronic active hepatitis and primary biliary cirrhosis. Scand J
8.
Watmough D, French MAH, Triger DR. Antibody response to tetanus toxoid in patients with primary biliary cirrhosis. J Clin Pathol 1987; 70:
Gastroenterol 1976; 11: 313-20.
683-86.
Esquivel CO, Van Thiel DH, Bernados A, et al. Liver transplantation for primary biliary cirrhosis. Gastroenterology 1988; 94: 1207-16. 10. Demetris AJ, Markus BH, Esquivel C, et al. Pathologic analysis of liver transplantation for primary biliary cirrhosis. Hepatology 1988; 8: 9.
939-47. 11. Sternerowicz R, Hopf U, Möller B, et al. Are antimitochondrial antibodies in primary biliary cirrhosis induced by R (rough)-mutants of Enterobacteriaceae? Lancet 1988; ii: 1166-70.
Zinc sandwich Why should primate growth hormones, unlike those of other vertebrates, have lactogenic activity? This question has puzzled endocrinologists for many years. Now Cunningham and his fellow protein engineers1 at Genentech in San Francisco think they may have found the answer-zinc. This trace metal is already known to be an essential component of the zinc finger regulatory proteins of the steroid receptor superfamily that includes oestrogen, progesterone, thyroid hormone, and 1,25-dihydroxyvitamin D receptors.2,3 These are cytoplasmic receptors and the hormones must pass through the plasma membrane to interact with them. By contrast, peptide hormones
274
their effects by combining with specific cellsurface receptors. Non-primate growth hormones show weak or undetectable binding to extracellular prolactin receptors. The Genentech researchers began their investigations by cloning the binding domain of the human prolactin receptor and then established that 50 jmol/1 zinc chloride enhanced the binding affinity of human growth hormone (hGH) for this extracellular receptor 8000-fold. Binding of hGH to the hGH receptor and of human prolactin to the prolactin receptor was not zinc dependent. Probable zinc ligands were shown to be a three-residue clusterHis, HisZl, and Glul74-in the hGH receptor and Hisl88 in the human prolactin receptor; non-primate growth hormones contain His21 and Glu 174 but instead of HisI8 they have Gln18. The hormone receptor zinc sandwich not only explains why non-primate growth hormones do not have lactogenic activity but also may shed light on other endocrine effects of zinc-eg, the link between zinc deficiency and growth retardation. Since growth hormone and prolactin receptors belong to the same family as peptide regulatory factor receptors, zinc may mediate receptor interaction of the interleukins, erythropoietin, and colony stimulating factors. exert
1.
Cunningham BC, Bass S, Fuh G, Wells JA. Zinc mediation of the binding of human growth hormone to the human prolactin receptor.
Science 1990; 250: 1709-12. 2. Evans RM. The steroid and thyroid hormone receptor superfamily. Science 1988; 240: 889-95. 3. Editorial. Zinc fingers and vitamin D resistance. Lancet 1989; i: 478.
Placental localisation in early pregnancy When women undergo ultrasound scanning in early pregnancy to clarify the gestational age or to screen for structural malformation in the fetus, an incidental finding may be a low-lying placenta-the placenta reaches or overlies the cervical os in 5%1,2 to 26 %of cases. That the frequency is lower if the initial scan is conducted at 20 weeks than if it is done early4 does not seem to explain all of this variation. Different criteria may have been used to categorise cases; researchers who describe a placenta as low lying only if it is seen to cover the cervical os, at least partly, report a frequency of 5-6%.12 Very few of the women identified in this way will have placenta praevia at delivery, presumably because growth of the uterus outstrips that of the placenta. Nevertheless, it has been arguedl,2,4-6 that they should be rescanned for placental site in the third trimester, at 28-36 weeks. This argument is based on a delivery frequency of placenta praevia of 2’3%4 to 16-9% in this group, compared with the population frequency of less than 1%. It is not clear why there should be such a large variation in the rate at which the condition is present at delivery in women diagnosed initially as high risk.
Other workers who have carried out prospective studies have concluded that, because so few women found to have a low placenta on the first scan still manifest the condition at delivery (2%,’ 0%1-3%), third-trimester scanning for this group cannot be justified unless there are clinical indications such as vaginal bleeding or unstable lie. These studies also provided data on whether all the clinical cases of placenta praevia noted in hospital had been diagnosed by the booking scan. Mc Clure and Doman,3 who conducted the largest and most recent study (also the one with the highest rate of low-lying placenta on initial ultrasound scanning), found that only 18 of 30 clinical cases had been so predicted, and agreed with previous proposals that a low-lying placenta on the initial scan should be ignored. Because of the high morbidity associated with placenta praevia and because bleeding does not necessarily occur before the onset of labour,l the possibility of early detection is attractive. However, the sensitivity and specificity of low-lying placenta on the first scan, as a test for clinical placenta praevia at delivery, are very poor. Many women, informed of the result and asked to reattend, become unduly worried that, if the repeat scan still shows a low-lying placenta, they may be advised to restrict activity, or be admitted. Placental localisation is important in women who have appreciable or recurrent vaginal bleeding and in those with an unstable lie in late pregnancy. The index of suspicion should be higher in older women of high parity, especially if there is a history of caesarean section9-11 (because such patients have an enhanced risk of placenta praevia and placenta accreta) and in those with a history of placenta praevia.12 Placental localisation at the initial scan cannot be recommended, and when a low placenta is noted incidentally, it is not necessary routinely to order a third-trimester scan. N, Doran TA, Miskin M, Benzie RJ, Ford JA. Natural history of placenta previa ascertained by diagnostic ultrasound. Am J Obstet Gynecol 1979; 133: 287-91. 2. Varma TR. The implications of low implantation of the placenta detected by ultrasonography in early pregnancy. Acta Obstet Gynaecol Scand 1. Rizos
1981; 60: 265-68. 3. McClure N, Dornan JC. Early identification of placenta praevia. Br J Obstet Gynaecol 1990; 97: 959-61. 4. Comeau J, Shaw L, Marcell CC, Lavery JP. Early placenta previa and delivery outcome. Obstet Gynecol 1983; 61: 577-80. 5. Royal College of Obstetricians and Gynaecologists. Report of the RCOG Working Party on Routine Ultrasound Examination in Pregnancy. London: RCOG, 1984. 6. Langlois SL, Miller AG. Placenta praevia: a review with emphasis on the role of ultrasound. Aust NZ J Obstet Gynaecol 1989; 29: 110-16. 7. Ruparelia BA, Chapman MG. Early low-lying placentae—ultrasonic assessment, progress and outcome. Eur J Obstet Gynecol Reprod Biol 1985; 20: 209-13. 8. Anderson ES, Steinke NM. The clinical significance of asymptomatic midtrimester low placenta diagnosed by ultrasound. Acta Obstet Gynaecol Scand 1988; 67: 339-41. 9. Singh PM, Rodrigues C, Gupta AN. Placenta praevia and previous caesarean section. Acta Obstet Gynaecol Scand 1981; 292: 371-72. 10. Breen JL, Neubecker R, Gregori CA, Franklin JE. Placenta accreta, increta and percreta: a survey of 40 cases. Obstet Gynecol 1977; 49: 43-47. 11. Clark SL, Koonings PP, Phelan JP. Placenta previa/accreta and prior cesarean section. Obstet Gynecol 1985; 66: 89-92. 12. Godoreski IG, Bahari CM, Schachter A, Neri A. Recurrent placenta previa. Eur J Obstet Gynecol Reprod Biol 1981; 12: 7-11.
